6cfo

HUMAN PYRUVATE DEHYDROGENASE E1 COMPONENT COMPLEX WITH COVALENT TDP ADDUCT ACETYL PHOSPHINATE

spinqualitylabelsall models 6cfo, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6cfo is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.7Å Ligands: A5X, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ODPB_HUMAN Defects in PDHB are the cause of pyruvate dehydrogenase E1-beta deficiency (PDHBD) [MIM:614111. An enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis. Function ODPB_HUMAN The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle. Publication Abstract from PubMed The pyruvate dehydrogenase multienzyme complex (PDHc) connects glycolysis to the tricarboxylic acid cycle by producing acetyl-CoA via the decarboxylation of pyruvate. Because of its pivotal role in glucose metabolism, this complex is closely regulated in mammals by reversible phosphorylation, the modulation of which is of interest in treating cancer, diabetes, and obesity. Mutations such as that leading to the alphaV138M variant in pyruvate dehydrogenase, the pyruvate-decarboxylating PDHc E1 component, can result in PDHc deficiency, an inborn error of metabolism that results in an array of symptoms such as lactic acidosis, progressive cognitive and neuromuscular deficits, and even death in infancy or childhood. Here we present an analysis of two X-ray crystal structures at 2.7 A resolution, the first of the disease-associated human alphaV138M E1 variant and the second of human wild-type (WT) E1 with a bound adduct of its coenzyme thiamin diphosphate (ThDP) and the substrate analogue acetylphosphinate (AcPhi). The structures provide support for the role of regulatory loop disorder in E1 inactivation, and the alphaV138M variant structure also reveals that altered coenzyme binding can result in such disorder even in the absence of phosphorylation. Specifically, both E1 phosphorylation at alphaSer264 and the alphaV138M substitution result in disordered loops that are not optimally oriented or available to efficiently bind the lipoyl domain of PDHc E2. Combined with an analysis of alphaV138M activity, these results underscore the general connection between regulatory loop disorder and loss of E1 catalytic efficiency. Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the alphaV138M variant of human pyruvate dehydrogenase.,Whitley MJ, Arjunan P, Nemeria NS, Korotchkina LG, Park YH, Patel M, Jordan F, Furey WF J Biol Chem. 2018 Jul 3. pii: RA118.003996. doi: 10.1074/jbc.RA118.003996. PMID:29970614 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pyruvate dehydrogenase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA